Dietary restriction gives fruit flies a rhythm for a long life

Research on circadian clocks identifies critical role for peripheral clock genes in fat metabolism and aging and presents new targets for drug development

November 18, 2015/Novato, CA Dietary restriction enhances the expression of the circadian clock genes in the peripheral tissue of fruit flies, according to research from the Kapahi lab at the Buck Institute. Publishing in Cell Metabolism, theresearchers show that dietary restriction, induced by reducing protein in the diet, increased the amplitude of circadian clocks and enhanced the cycles of fat breakdown and fat synthesis. This improvement in fat metabolism may be a key mechanism in explaining why dietary restriction extends lifespan in several species, including the flies in this study.

The research also presents a tantalizing possibility for humans eager to take a drug that would allow them to reap the health benefits of dietary restriction without going on an extreme diet. When scientists genetically altered the flies to boost clock function the animals lived longer, even when they ate whatever they wanted to. On the other hand, disrupting the clocks, either genetically or by keeping the flies under constant light, made the animals irresponsive to the beneficial effects of dietary restriction.

“More than 10-15% of the genome is under circadian control, especially genes which regulate processes involving cellular repair and metabolism,” said senior scientist and Buck professor Pankaj Kapahi, PhD. “Every cell has a clock and the action of clocks in peripheral tissues –fat, intestines, kidneys – plays an important role in modulating metabolism and thereby mediating lifespan extension via dietary restriction.”

Previous work from the Kapahi lab showed that flies on a lifespan-extending Spartan diet exhibited an enhanced turnover of triglycerides. This new work, also led by Buck assistant research professor Subhash D. Katewa, PhD, suggests a role for timeless, a circadian clock gene, in the cycling of specific medium chain triglycerides under dietary restriction. “The role of medium chain triglycerides in aging and regulation of clock functions is not clear, however dietary medium chain triglycerides have been associated with weight loss and improved healthspan in both humans and mice,” said Katewa, noting current consumer interest in coconut oil which is rich in medium chain triglycerides. “Our work demonstrates for the first time that medium chain triglyceride synthesis in animals is under nutritional and circadian control,” he said. “If we want to modulate the effects of nutrient manipulation on fat metabolism and aging then targeting the activity of peripheral circadian clocksgives us a way to achieve that goal.”

“Circadian rhythms, which impact many behaviors like sleep or cellular processes like metabolism, tend to dampen with age,” said Kapahi. “The metabolic rhythms of flies on dietary restriction maintain a remarkable robustness as they age, which we think helps them live longer. It is exciting to contemplate how this mechanism might be exploited for human health.”

Other Buck researchers involved in the study include: Kazutaka Akagi, Neelanjan Bose, Timothy Camarella, David Hall, Sonnet Davis, Christopher S. Nelson, Rachel B. Brem and Arvind Ramanathan. Other collaborators include Kuntol Rakshit and Jadwiga M. Giebultowicz from The Department of Integrative Biology, Oregon State University, Corvallis, OR; and Xiangzhong Zheng and Amita Sehgal, Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. This work was funded by grants from the American Federation of Aging Research, Larry L. Hillblom Foundation, the National Institutes of Health (R01AG038688, AG038012 and AG045835) and from the Ellison Medical Foundation.

About the Buck Institute for Research on Aging

The Buck Institute is the U.S.’s first independent research organization devoted to Geroscience – focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending “Healthspan”, the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer’s and Parkinson’s, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: www.thebuck.org